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HIGS

A collaboration among scientists from academia, industry, and government

The Hemophilia Inhibitor Genetics Study (HIGS) is an international investigation that combines the strengths of family and association studies to identify and confirm relationships between genetic factors and the development of inhibitory antibodies to factor VIII. Data and samples contributed by 44 hemophilia treatment centers in Europe, North America, Latin America, and South Africa. The cohort is composed of brother pairs concordant for a history of inhibitors, or discordant (one with an inhibitor, the other without) and a group on singletons with inhibitors, and their parents. In work recently completed, HIGS was joined by two previously described cohorts – the Hemophilia Growth and Development Study and the Malmö International Brother Study – in the evaluation of a large panel of single nucleotide polymorphisms (SNPs) to identify markers associated with inhibitor history. Currently in progress is a replication and confirmatory step to validate associations observed. Also underway is a Transmission Disequilibrium Test (TDT), a powerful analytic strategy developed by Robert Elston (1998). This test requires two parents and an affected offspring to test for distortions from expectations in the transmission of alleles from each heterozygous parent to the affected child.

Since the start of HIGS, three events of direct impact to the project have occurred. First, genotyping costs have decreased considerably. Second, knowledge of the genome has expanded with the completion of the HapMap project, the annotation of the human genome, and the availability of both structural variation and single nucleotide polymorphisms in public databases. The third event was facilitated by a peer review conducted at the Laboratory of Genomic Diversity of the National Cancer Institute (NCI) in Frederick, MD, at the onset of the study (2003). With HIGS singled out as a well-designed study and a project of scientific significance by the NCI Board of Scientific Counselors, a successful (and unprecedented) argument was made to grant the study a special status, allowing HIGS, a commercially funded investigation, to take advantage of lower cost government rates for purchase of reagents and study materials, and gain access to laboratory testing platforms, equipment, and technical and scientific support at no cost to the study. The effect of these events has been to permit powerful but affordable analysis.

HIGS is supported by an investigator-initiated grant from Baxter BioScience, and in part with federal funds from the National Institutes of Health, National Cancer Institute, N01-CO-12400. The Malmö International Brother Study is funded through grants from Wyeth and the Research Fund at Malmö University Hospital. The Hemophilia Growth and Development Study is funded by the National Institutes of Health, National Institute of Child Health and Human Development, R01-HD-41224. For questions about this study, please contact Sharyne Donfield at sdonfield@rhoworld.com.